Compounds for the inhibition of herpes viruses

摘要

3D protein modeling and virtual screening of commercially-available compounds were performed to identify new inhibitors of the herpesvirus DNA polymerase, a key enzyme in the viral replication cycle. Two compounds (Nos 2 and 9) were particularly active against HSV-1 and HSV-2 strains and one compound (No 3) inhibited specifically cytomegalovirus (CMV) strains (overall hit rate of 25%). Some of the tested compounds inhibited wild-type viruses and strains resistant to current antiviral agents. New chemical entity derivatives of compound 2 with binding potential to the DNA polymerase retained an excellent activity against HSV-1, HSV-2 and VZV like the parental compound, as well against strains resistant to current antiviral agents. These non-nucleosidic herpesvirus DNA polymerase inhibitors with in vitro activity against drug-resistant clinical isolates warrant further pre-clinical studies.

主权项

1. A pharmaceutical composition comprising a compound of formula IA or formula IB or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier: wherein R is selected from the group consisting of unsubstituted phenyl or a substituted phenyl of formula II: an unsubstituted pyridine or a substituted pyridine selected from the group consisting of: a pyrimidine selected from the group consisting of: wherein X and Y each are independently selected from the group consisting of H, —OR1, NH2, F, Cl, Br, I, an alkyl group of 1 to 3 carbon atoms and an allyl group; and wherein R1 is selected from the group consisting of H and an alkyl group of 1 to 3 carbon atoms, provided that said compound of formula IA is not